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  • HUMAN-PAPILLOMAVIRUS  (4)
Keywords
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; BLOOD ; CELL ; Germany ; human ; VITRO ; NEW-YORK ; POPULATION ; PROTEIN ; cell line ; LINES ; PATIENT ; RESPONSES ; IFN-GAMMA ; DONOR ; ANTIGENS ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; CELL-LINES ; E7 ; papillomavirus ; LIMITATION ; STIMULATION ; TARGET ; ASSAY ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; TYPE-16 ; GENOTYPES ; HPV ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; POPULATIONS ; ONCOPROTEIN ; VACCINE ; CANCER-PATIENTS ; CD8(+) ; ELISPOT ; EPITOPE ; EPITOPES ; IMMUNOTHERAPY ; intraepithelial neoplasia ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; E7 ONCOPROTEIN ; IMMUNOGENICITY ; TARGETS ; INTERFERON-GAMMA ; 14 HIGH-RISK ; ENZYME-IMMUNOASSAY ; HUMAN BLOOD ; immunotherapy,T cell response,cytotoxic T cell,uterine cancer,tumor infiltrating lymphocytes ; INFILTRATING LYMPHOCYTES
    Abstract: Purpose. Human papillomavirus (HPV) type 16 and 18 are the most prevalent genotypes in cervical cancers. The viral oncoproteins E6 and E7 are considered to be tumor-specific targets for immunotherapy. HPV E7 antigen-loaded dendritic cells (DC) were evaluated as cellular tumor vaccine. Methods. Autologous monocyte-derived DCs loaded with recombinant HPV16 or HPV18 E7 oncoprotein were used to induce in vitro a specific T cell response. Specificities of activated T cells were determined. Results. E7-specific T cells could be identified in 18/20 T cell lines from healthy blood donors. CD4(+) T cell responses (13/16) were found by proliferation assay. CD8(+) CTLs (12/18) were detectable by interferon-gamma (IFN-gamma) ELISpot analysis. Seven donors reacted in both assays and only 2/20 T cell lines did not react in any assay. Thus, specific T cells could be activated in 〉80% of healthy individuals. T cell lines from suitable donors were specific for HLA-A*0201-restricted epitopes. Furthermore, HPV E7 antigen-loaded DC stimulated specific responses in freshly isolated tumor infiltrating lymphocyte (TIL) populations of cervical cancer patients. Conclusion. Autologous dendritic cells loaded with HPV E7 protein can induce T cell responses in healthy individuals by in vitro stimulation and evoke responses in TIL from cervical cancer biopsies. Since there are no limitations with respect to specific HLA-haplotypes, these findings may be a basis for the development of a therapeutic protein-based DC tumor vaccine against cervical cancer for HPV16- and HPV18-positive patients
    Type of Publication: Journal article published
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  • 2
    Keywords: CANCER ; CELLS ; IN-VITRO ; tumor ; Germany ; human ; IN-VIVO ; THERAPY ; VITRO ; SYSTEM ; DISEASE ; RISK ; GENE ; GENE-TRANSFER ; DNA ; INFECTION ; INDUCTION ; ANTIGEN ; DENDRITIC CELLS ; T cells ; T-CELLS ; E7 ; OPEN READING FRAME ; papillomavirus ; HUMANS ; ASSAY ; WOMEN ; cervical cancer ; CERVICAL-CANCER ; human papillomavirus ; HIGH-RISK ; ONCOGENE ; TRANSFORMATION ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; SAFETY ; EPITOPE ; IMMUNOTHERAPY ; PLASMID DNA ; IMMUNODEFICIENCY-VIRUS TYPE-1 ; IMMUNIZATION ; MUTATIONAL ANALYSIS ; ASSAYS ; cytotoxic T lymphocyte ; BACTERIAL-DNA ; RISK-FACTOR ; in vivo ; tumor regression ; tumor protection ; ENHANCED IMMUNOGENICITY ; gene shuffling ; HPV16 E7 ; in vitro immunization
    Abstract: Anew and very promising approach in vaccine development is the application of naked DNA. In comparison to conventional vaccines it offers several advantages, especially if there is a need for the development of low cost vaccines. Infection with high-risk human papillomaviruses (hr-HPVs) is the major risk factor for the development of cervical cancer (cc), the third most common cancer in women worldwide. The HPV E7 oncogene is constitutively expressed in HPV-infected cells and represents an excellent target for immune therapy of HPV-related disease. Therefore, we chose the HPV-16 E7 as model antigen in the development of a therapeutic DNA vaccine candidate. For safety reasons the use of a transforming gene like the HPV-16 E7 for DNA vaccination is not feasible in humans. In consequence we have generated an artificial ("shuffled") HPV-16 E7-gene (HPV-16 E7SH), containing all putative cytotoxic T-lymphocyte (CTLs) epitopes and exhibiting high safety features. Here, we show the induction of a strong E7-wildtype (E7WT) directed cellular and humoral immune response including tumor protection and regression after in Vivo immunization in the murine system. Moreover, the vaccine candidate demonstrated immunogenicity in humans, demonstrated by priming of antigen-specific T cells in vitro. Importantly, the artificial HPV-gene has completely lost its transforming properties as measured in soft agar transformation assays. These results may be of importance for the development of vaccines based on oncogenes or oncoproteins. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16472545
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; radiotherapy ; tumor ; CELL ; Germany ; human ; TOXICITY ; NEW-YORK ; PROTEIN ; TUMORS ; PATIENT ; RESPONSES ; IFN-GAMMA ; INDUCTION ; DENDRITIC CELLS ; T cell ; T-CELL ; T-CELLS ; E7 ; papillomavirus ; IMMUNE-RESPONSES ; TARGET ; STAGE ; ASSAY ; cervical cancer ; CERVICAL-CANCER ; MARKERS ; human papillomavirus ; TYPE-16 ; GENOTYPES ; HPV ; E6 ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; ONCOPROTEIN ; VACCINE ; CANCER-PATIENTS ; SAFETY ; ELISPOT ; immune response ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; vaccination ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; SERIES ; CARCINOMA SCC ANTIGEN ; DE-NOVO ; E7 ONCOPROTEIN ; HLA ; IMMUNOGENICITY ; immunotherapy,ELISpot,T lymphocytes,CTL,uterine cancer ; STAGE IB ; TARGETS ; tumor marker
    Abstract: Purpose. Human papillomavirus (HPV) type 16 and 18 are the most prevalent genotypes in cervical cancer. The viral oncoproteins E6 and E7 are considered to be tumor-specific targets for immunotherapy. HPV E7 antigen-loaded autologous dendritic cells (DC) were evaluated as cellular tumor vaccine in a case series of cervical cancer patients. Methods. Autologous monocyte-derived DCs were pulsed with recombinant HPV16 E7 or HPV18 E7 oncoprotein and administered to 15 stage IV cervical cancer patients. Safety, toxicity, and induction of serological and cellular immune responses were monitored. Results. The vaccine was well-tolerated and no local or systemic side effects or toxicity were recorded. A specific serologic response was seen in 3/11 evaluated patients. Specific cellular immune responses (4/11) were detected with 2/10 positive de novo reactions plus one boosted preexistent response in proliferation assays and 3/11 in IFN-gamma ELISpot assays. A transient drop in tumor marker SCC was observed in 5/9 evaluable patients but did not correlate with markers of the immune response. No objective clinical response was observed. Tumor biopsies available from four patients showed severe or complete loss of HLA expression in three of the advanced tumors. Conclusion. Autologous dendritic cells pulsed with HPV E7 protein can induce T cell responses in a portion of late stage cervical cancer patients. Boosting of immune responses by adjuvants and vaccination of tumor HLA-positive patients will be mandatory in future trials
    Type of Publication: Journal article published
    PubMed ID: 12898233
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  • 4
    Keywords: PEPTIDE ; RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; VITRO ; MOLECULES ; TISSUE ; ACCUMULATION ; LINES ; ACTIVATION ; LIGAND ; CONTRAST ; T-CELLS ; CELL-LINES ; DOWN-REGULATION ; MOLECULE ; TARGET ; IN-SITU ; NEOPLASIA ; PROGRESSION ; NUMBER ; cervical cancer ; cervical intraepithelial neoplasia ; CERVICAL-CANCER ; CELL-LINE ; LYMPHOCYTES ; PEPTIDES ; LIGANDS ; CLASS-I ; HUMAN-PAPILLOMAVIRUS ; NATURAL-KILLER-CELLS ; NK cells ; EPITHELIAL-CELLS ; CERVICAL-CARCINOMA ; CARCINOMAS ; PROGNOSTIC-SIGNIFICANCE ; IMMUNOTHERAPY ; intraepithelial neoplasia ; T-LYMPHOCYTES ; T lymphocyte ; BIOPSY ; T lymphocytes ; ONCOLOGY ; RE ; USA ; LOSSES ; NKG2D RECEPTOR ; viral ; NOV ; NK-CELLS ; NKG2D ligands ; DNAM-1 ligands ; I-RELATED CHAIN ; PARTICLE VACCINE ; QUADRIVALENT VACCINE
    Abstract: Human papillomavirus-induced cervical carcinomas often show impaired expression of MHC class I molecules resulting in the inability of tumor cells to directly present viral peptides to cytotoxic T lymphocytes. Loss of MHC class I expression combined with the expression of activating NK cell receptor ligands renders tumor cells potentially susceptible to NK cell attack. Thus, in this study, we analyzed the expression of activating NK cell receptor ligands, NK cell accumulation and activation status in situ in normal ectocervical tissue (NCT), cervical intraepithelial neoplasia (CIN) and squamous cervical carcinoma (CxCa). We observed that expression of the DNAM-I ligand CD155 was frequently upregulated in CxCa, but not in CIN. The NKG2D ligand MICA was upregulated in fewer CxCa biopsies. In contrast, another NKG2D ligand ULBP2 was preferentially expressed in differentiated epithelial cells of NCT. Increased numbers of NK cells were detected in CIN as compared to NCT and CxCa. Expression of activating NK cell receptor ligands combined with loss of MHC class I was not correlated with enhanced NK cell accumulation or activation status. Furthermore, we demonstrate that cervical cancer cell lines are killed by the NK cell line, NKL, in a NKG2D- and DNAM-1-dependent manner in vitro. Since a significant number of CxCa biopsies showed low MHC class I expression combined with high expression of one or more of the tested activating NK cell receptor ligands, we conclude that CxCa might be a promising target for NK cell-based adoptive immunotherapy. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18712710
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